The Coma Recovery Scale Revised (CRS-R) is considered as the most sensitive scale to assess patients with disorders of consciousness (DOC). Guidelines recommend repeated assessments because patients might ... [more ▼]

The Coma Recovery Scale Revised (CRS-R) is considered as the most sensitive scale to assess patients with disorders of consciousness (DOC). Guidelines recommend repeated assessments because patients might suffer from consciousness fluctuations, but it is not specified how many assessments are needed. The present study included 131 patients with DOC. They have been assessed at least 6 times during a 14-days period with the CRS-R. Results show that 5 CRS-R assessments are needed to reach a reliable diagnosis, and that all the CRS-R subscales are influenced by consciousness fluctuations. We here showed that consciousness fluctuations influence the behavioral diagnosis, and that 5 assessments within a short period of time are needed to get a reliable clinical diagnosis. [less ▲]

Introduction: The mildly invasive 18F-ﬂuorodeoxyglucose positron emission tomography (FDG-PET) is a well-established imaging technique to measure ‘resting state’ cerebral metabolism. This technique made it possible to assess changes in metabolic activity in clinical applications, such as the study of severe brain injury and disorders of consciousness. Objective: We assessed the possi- bility of creating functional MRI activity maps, which could estimate the rela- tive levels of activity in FDG-PET cerebral metabolic maps. If no metabolic absolute measures can be extracted, our approach may still be of clinical use in centers without access to FDG-PET. It also overcomes the problem of recogniz- ing individual networks of independent component selection in functional mag- netic resonance imaging (fMRI) resting state analysis. Methods: We extracted resting state fMRI functional connectivity maps using independent component analysis and combined only components of neuronal origin. To assess neu- ronality of components a classiﬁcation based on support vector machine (SVM) was used. We compared the generated maps with the FDG-PET maps in 16 healthy controls, 11 vegetative state/unresponsive wakefulness syndrome patients and four locked-in patients. Results: The results show a signiﬁcant similarity with q = 0.75  0.05 for healthy controls and q = 0.58  0.09 for vegetative state/unresponsive wakefulness syndrome patients between the FDG- PET and the fMRI based maps. FDG-PET, fMRI neuronal maps, and the conjunction analysis show decreases in frontoparietal and medial regions in vegetative patients with respect to controls. Subsequent analysis in locked-in syndrome patients produced also consistent maps with healthy controls. Conclusions: The constructed resting state fMRI functional connectivity map points toward the possibility for fMRI resting state to estimate relative levels of activity in a metabolic map. [less ▲]

A recent study showed that single-session anodal transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (LDLPF) transiently improves consciousness in 43% of patients in minimally conscious state (MCS) (Thibaut et al., 2014). We here test the potential effects and safety of repeated tDCS in severely brain-damaged patients with MCS. In this double-blind cross-over sham-controlled experimental design, we delivered two sessions of repeated (5 days of stimulation) tDCS, either anodal or sham in a randomized order. We stimulated the LDLPF cortex during twenty minutes in 20 MCS patients (12 men, aged 48±16 years, time since onset 78±95 months, 12 post-traumatic). Consciousness was assessed by the French adaptation of the Coma Recovery Scale Revised (CRS-R; Schnakers et al., 2008) before and after each stimulation. A treatment effect was observed for the comparison between CRS-R total scores at baseline and after 5 days of real tDCS (p<0.01). Behaviorally, 10/20 patients showed a tDCS-related improvement; 5 patients responded after the first stimulation and 5 other patients responded after 2, 3 or 4 days of stimulation. No side effect (e.g. epilepsy) was reported. Our results demonstrate that repeated (5 days) anodal LDLPF tDCS is safe and might improve signs of consciousness in about half of patients in MCS. It is important to note that the first session is not predictive for a future positive effect of the efficacy of the non-invasive electrical stimulation. [less ▲]

BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of ... [more ▼]

BACKGROUND: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). METHODS: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). RESULTS: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. CONCLUSION: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS. [less ▲]

The past 15years have provided an unprecedented collection of discoveries that bear upon our scientific understanding of recovery of consciousness in the human brain following severe brain damage ... [more ▼]

The past 15years have provided an unprecedented collection of discoveries that bear upon our scientific understanding of recovery of consciousness in the human brain following severe brain damage. Highlighted among these discoveries are unique demonstrations that patients with little or no behavioral evidence of conscious awareness may retain critical cognitive capacities and the first scientific demonstrations that some patients, with severely injured brains and very longstanding conditions of limited behavioral responsiveness, may nonetheless harbor latent capacities for recovery. Included among such capacities are particularly human functions of language and higher-level cognition that either spontaneously or through direct interventions may reemerge even at long time intervals or remain unrecognized. When patients in “persistent vegetative state” (recently also coined unresponsive wakefulness syndrome) show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients' behaviors: MCS+ describes high-level behavioral responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS- describes low-level behavioral responses (i.e., visual pursuit, localization of noxious stimulation or contingent behavior such as appropriate smiling or crying to emotional stimuli). Patients who show non-behavioral evidence of consciousness or communication only measurable via ancillary testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness. Taken together, recent studies show that awareness is an emergent property of the collective behavior of frontoparietal top-down connectivity. Within this network, external (sensory) awareness depends on lateral prefrontal/parietal cortices while internal (self) awareness correlates with precuneal/mesiofrontal midline activity. Of clinical importance, this knowledge now permits to improve the diagnosis, prognosis and treatment of patients with disorders of consciousness, which currently remains very challenging. New technological advances now also permit to show command-specific changes in fMRI, EEG or eye-pupil measurements providing motor-independent evidence of conscious thoughts and in come cases even of communication. We will conclude by discussing related ethical issues and the challenge of improving our clinical care and quality of life in these challenging patients with disorders of consciousness. [less ▲]

Background: Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI). Methods: For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale—Revised (CRS—R), cerebral 18F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS—R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale—Extended. Findings: We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). 18F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85—98) and high congruence (85%, 77—90) with behavioural CRS—R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30—61) and had lower overall congruence with behavioural scores (63%, 51—73) than PET imaging. 18F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64—81), and fMRI in 36 of 65 patients (56%, 43—67). 13 of 42 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS—R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness. Interpretation: Cerebral 18F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate. Funding: The Belgian National Funds for Scientific Research (FNRS), Fonds Léon Fredericq, the European Commission, the James McDonnell Foundation, the Mind Science Foundation, the French Speaking Community Concerted Research Action, the University of Copenhagen, and the University of Liège. [less ▲]

Zolpidem has been reported as an "awakening drug" in some patients with disorders of consciousness (DOC). We here present the results of a prospective openlabel study in chronic DOC patients. Sixty ... [more ▼]

Zolpidem has been reported as an "awakening drug" in some patients with disorders of consciousness (DOC). We here present the results of a prospective openlabel study in chronic DOC patients. Sixty patients (35±15 years; 18 females; mean time since insult ± SD: 4±5.5 years; 31 with traumatic etiology) with a diagnosis of vegetative state/unresponsive wakefulness syndrome (n=28) or minimally conscious state (n=32) were behaviorally assessed using the Coma Recovery Scale-Revised (CRS-R) before and one hour after administration of 10 mg of zolpidem. At the group level, the diagnosis did not change after intake of zolpidem (p=0.10) and CRS-R total scores decreased (p=0.01). Twelve patients (20%) showed improved behaviors and/or CRS-R total scores after zolpidem administration but in only one patient was the diagnosis after zolpidem intake found to show a significant improvement (functional object use), which suggested a change of diagnosis. However, in this patient, a double-blind placebo-controlled trial was performed in order to better specify the effects of zolpidem, but the patient, on this trial, failed to show any clinical improvements. The present open-label study therefore failed to show any clinically significant improvement (i.e., change of Effect of zolpidem in chronic disorders of consciousness: a prospective open-label study diagnosis) in any of the 60 studied chronic DOC patients. [less ▲]

OBJECTIVES: The aim of this study was to determine whether the assessment of pursuit eye movements in patients in minimally conscious state (MCS) is influenced by the choice of the visual stimulus (study ... [more ▼]

OBJECTIVES: The aim of this study was to determine whether the assessment of pursuit eye movements in patients in minimally conscious state (MCS) is influenced by the choice of the visual stimulus (study 1) and by the moving plane (study 2). METHODS: Patients with MCS (MCS- and MCS+) in the acute (<1 month post-injury) or chronic (>1 month) setting were assessed. The Coma Recovery Scale-Revised (CRS-R) procedure was used to test visual pursuit of a moving mirror, object and person (study 1, n = 88) and to test vertical and horizontal visual tracking (study 2, n = 94). RESULTS: Study 1: Patients with visual pursuit tracked preferentially the moving mirror over the moving person or object. Study 2: Patients displaying visual pursuit, especially in MCS- and in chronic setting, preferentially tracked on the horizontal rather than the vertical plane. CONCLUSION: The findings confirm the importance of using a mirror to assess visual pursuit in patients in MCS and of initiating testing using the horizontal plane, specifically in patients in MCS- and those in chronic setting. Assessment should then be done on the vertical plane if visual pursuit is not detected on the horizontal plane. [less ▲]

Major clinical endpoints of general anesthesia, such as the alteration of consciousness, are achieved through effects of anesthetic agents on the central nervous system, and, more precisely, on the brain ... [more ▼]

Major clinical endpoints of general anesthesia, such as the alteration of consciousness, are achieved through effects of anesthetic agents on the central nervous system, and, more precisely, on the brain. Historically, clinicians and researchers have always been interested in quantifying and characterizing those effects through recordings of surface brain electrical activity, namely electroencephalography (EEG). Over decades of research, the complex signal has been dissected to extract its core substance, with significant advances in the interpretation of the information it may contain. Methodological, engineering, statistical, mathematical, and computer progress now furnishes advanced tools that not only allow quantification of the effects of anesthesia, but also shed light on some aspects of anesthetic mechanisms. In this article, we will review how advanced EEG serves the anesthesiologist in that respect, but will not review other intraoperative utilities that have no direct relationship with consciousness, such as monitoring of brain and spinal cord integrity. We will start with a reminder of anesthestic effects on raw EEG and its time and frequency domain components, as well as a summary of the EEG analysis techniques of use for the anesthesiologist. This will introduce the description of the use of EEG to assess the depth of the hypnotic and anti-nociceptive components of anesthesia, and its clinical utility. The last part will describe the use of EEG for the understanding of mechanisms of anesthesia-induced alteration of consciousness. We will see how, eventually in association with transcranial magnetic stimulation, it allows exploring functional cerebral networks during anesthesia. We will also see how EEG recordings during anesthesia, and their sophisticated analysis, may help corroborate current theories of mental content generation. [less ▲]

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc ... [more ▼]

The differentiation of the vegetative or unresponsive wakefulness syndrome (VS/UWS) from the minimally conscious state (MCS) is an important clinical issue. The cerebral metabolic rate of glucose (CMRglc) declines when consciousness is lost, and may reveal the residual cognitive function of these patients. However, no quantitative comparisons of cerebral glucose metabolism in VS/UWS and MCS have yet been reported. We calculated the regional and whole-brain CMRglc of 41 patients in the states of VS/UWS (n = 14), MCS (n = 21) or emergence from MCS (EMCS, n = 6), and healthy volunteers (n = 29). Global cortical CMRglc in VS/UWS and MCS averaged 42% and 55% of normal, respectively. Differences between VS/UWS and MCS were most pronounced in the frontoparietal cortex, at 42% and 60% of normal. In brainstem and thalamus, metabolism declined equally in the two conditions. In EMCS, metabolic rates were indistinguishable from those of MCS. Ordinal logistic regression predicted that patients are likely to emerge into MCS at CMRglc above 45% of normal. Receiver-operating characteristics showed that patients in MCS and VS/UWS can be differentiated with 82% accuracy, based on cortical metabolism. Together these results reveal a significant correlation between whole-brain energy metabolism and level of consciousness, suggesting that quantitative values of CMRglc reveal consciousness in severely brain-injured patients. [less ▲]

Positron emission tomography (PET) allows studies of cerebral metabolism and blood flow and has been widely used to investigate physiological mechanisms underlying altered states of consciousness. The aim ... [more ▼]

Positron emission tomography (PET) allows studies of cerebral metabolism and blood flow and has been widely used to investigate physiological mechanisms underlying altered states of consciousness. The aim of this chapter is to review the current literature on brain metabolism during physiological or pathological loss of consciousness including studies on disorders of consciousness arising from severe brain injury (vegetative/unresponsive or minimally conscious states), and related non-pathological conditions such as sleep and hypnotic states. Identifying brain areas specifically involved in conscious processing, these studies have contributed to our understanding of the underlying physiology of consciousness. The precuneal and cingulate cortices, for example, seem to be key areas for maintaining consciousness awareness. Other areas such as hypothalamus, amygdala or the temporo-occipital cortex seem to play a role in different states of unconsciousness such as rapid eye movement sleep and hypnosis. PET studies permit a better comprehension of the loss of consciousness, and focus the implication of specific neural areas and networks in pathologically (vegetative/unresponsive or minimally conscious states), physiologically (sleep), and hypnotically altered states of consciousness. [less ▲]